Myeloma Drugs May Help Build Bone

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Two proteasome inhibitors developed for treating multiple myeloma, including the FDA-approved drug carfilzomib, may also have directly beneficial effects on bone.

Note that both drugs blocked bone loss as well as decreasing tumor burden, and the effects of the drugs were generally more pronounced than those of the pioneer drug in this class, bortezomib.

Two proteasome inhibitors developed for treating multiple myeloma, including the FDA-approved drug carfilzomib, may also have directly beneficial effects on bone, researchers said.

Studies with carfilzomib (Kyprolis) and an investigational oral drug, oprozomib, in healthy mice indicated that these agents inhibit bone resorption and increase bone formation, independent of their effects against the abnormal hemopoietic cells responsible for myeloma, according to Katherine Weilbaecher, MD, of Washington University in St. Louis, and colleagues.

Their experiments also showed that, in mouse models of myeloma, both drugs blocked bone loss as well as decreasing tumor burden, the researchers wrote online in Leukemia. These effects of the drugs were generally more pronounced than those of the pioneer drug in this class, bortezomib (Velcade).

Led by bortezomib, proteasome inhibitors have become a staple treatment for multiple myeloma. They inhibit proliferation of myeloma cells and promote their death, and also alter their interaction with other cells within the bone marrow.

Such interactions are thought to be the root of the well-recognized bone complications of multiple myeloma, fostering the growth and activity of bone-resorbing osteoclasts and inhibiting their bone-building osteoblast counterparts.

The new animal studies by Weilbaecher and colleagues suggest that "zomib" drugs can counteract these latter effects by directly promoting osteoblasts and inhibiting osteoclasts, apart from their activity against myeloma cells.

"Our data demonstrate that carfilzomib and oprozomib effectively inhibit myeloma growth and shift the bone microenvironment from a catabolic to an anabolic state," the researchers wrote.

To start, they treated human myeloma cells in vitro with the two agents, confirming that they are capable of killing these cells, whether the drug exposure was continuous or intermittent -- the latter intended to reflect more realistically the exposure in clinical situations.

Other experiments with cultured cells showed that the zomib drugs inhibited osteoclast differentiation and activity, while also increasing differentiation of osteoblasts and promoting bone mineralization.

Weilbaecher and colleagues also conducted a series of experiments to confirm that these effects also occur with the drugs in vivo.

Intravenous treatment with carfilzomib and oral dosing of oprozomib in normal mice for 2 weeks led to increases in markers of bone formation, such as N-terminal propeptide of type I procollagen. Trabecular bone volume and density, as indicated in CT scans, also increased, the researchers reported.

All three drugs significantly decreased tumor burdens and were associated with changes in bone turnover markers reflective of reduced resorption and increased bone formation.

"Notably, although differences [between drugs] were not statistically significant, a trend toward increased N-terminal propeptide of type I procollagen activity with carfilzomib and oprozomib versus bortezomib was observed," Weilbaecher and colleagues wrote.

A similar study of oprozomib in mice injected with human myeloma cells also showed a decrease in tumor cells and evidence of bone anabolic activity with the oral drug.

Weilbaecher and colleagues called for clinical studies focusing on "bone turnover markers, bone mineral density, and documentation of skeletal events [which] would be of particular value to determine whether these new proteasome inhibitors obtain meaningful combined benefits on myeloma and associated bone disease."

The study was supported by the National Institutes of Health, the St. Louis Men's Group Against Cancer, the Holway Myeloma Fund, the Spanish MICINN-ISCII, the Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y Leon, the Spanish Myeloma Network Program, and the Spanish FIS.

One co-author was an employee of Onyx Pharmaceuticals, which supplied carﬁlzomib and oprozomib for this research.

Other authors declared no conflicts of interest.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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